Apoptosis, or programmed cell death, is an important physiological process in multicellular organisms, both during development and for homeostasis. Apoptosis permits the elimination of cells that are no longer necessary, that are produced in excess, that have developed improperly, or that have sustained genetic damage. Apoptosis occurs in many different tissue systems and must be properly regulated to maximize the benefit to the individual. Conversely, dysregulation of the apoptotic mechanism can result in the development of significant disease which results from either inhibition of and/or inappropriate cell death. For example, inhibition of cell death may contribute to disease in the immune system by allowing persistence of self-reactive B and T cells, thereby promoting autoimmune disorders. See, e.g., Watanabe-Fukunaga et al., Nature 356:314-317 (1992). Additionally, inhibition or failure of the cell death mechanism may permit such cells to undergo mutations leading to a transformed or cancerous state. See, e.g., Korsmeyer, Blood 80:879-886 (1992).
Apoptosis is mediated, at least in part, by a cell surface receptor protein, Fas, which plays an important role in the development and function of the immune system. Malfunction of the Fas system has been shown to cause lymphoproliferative disorders and accelerate autoimmune disorders. Takahashi et al., Cell 76:969-976 (1994). Further, exacerbation of Fas-mediated apoptosis has been implicated as leading to excessive tissue destruction. Ogasawara et al., Nature 364:806-809 (1993).
The Fas ligand (FasL) binds to and activates the Fas receptor to initiate the apoptotic mechanism. For an overview of Fas receptor mediated apoptosis, see, e.g, Nagata et al., Science 267:1449-1455 (1995). In normal physiological contexts, FasL exists predominantly as a type II membrane protein. Supraphysiological states, e.g., in vitro overexpression, or pathophysiological states, e.g., specific leukemias or lymphomas, exhibit some release of a proteolytically processed form of FasL. See, e.g., Tanaka et al., Nature Medicine 2:317-322 (1996). Additionally, production of a soluble form of FasL may occur upon activation of lymphocytes. Tanaka et al., EMBO J. 14:1129-1135 (1995). However, the prevalence of soluble FasL in vivo is not known.
It would generally be desirable to be able to produce a soluble compound that functions as the naturally occurring Fas ligand in its interactions with the Fas receptor, i.e., receptor binding and/or activation of receptor mediated pathways, for use in modeling this interaction as well as providing an external method of regulating this interaction. The present invention meets these and other needs.